Certain oxospiro hydroxyspiro indan-indolizines



United States Patent Cfi ice 3,189,611 Patented June 15, 1965 Thisinvention relates-to a new series of organic compounds. Moreparticularly, this invention relates to certain oxospiro andhydroxyspiro indan-indolizines and the methods for their preparation.

The compounds of the present invention maybe rep,- resentedby thefollowing structural formula:

wherein R is hydrogen or oxo and R is hydrogen, oxo; hydroxy oresterifiedhydroxy, e.g., lower alkylcarbonyloxy having 1 to 7 carbonatoms.

The compounds of the present invention in tests on animals have beenfound to possess valuable pharmacological properties. For example a 50mg./kg. of body weight dose of 1',5',6',7',8',8a-hexahydro-1-oxospiro(indan-2,2'-indoliz'ine) -3 (2H) -oue when administered orally to a ratshows significant protection against kaolininduced edema. The novelcompounds also show hypotensive and anti-inflammatory'activity whentested on animals. v

The compounds of this invention are prepared by Knoevenagel condensationof 2-pyridinecarboxaldehyde with a dialkyl malonate. A suitable basiccondensing agent forthisreaction is a secondary amine such asdibutylamine or, preferabl piperidiue. Advantageously, one may conductthe reaction in the presence of a weak organic acid such as acetic acidor benzoic acid.

The resultant dialkyl Z-pyridylmethylenemalonate is then hydrogenated byreacting it with hydrogen catalytically activated by a platinum,palladium or nickel catalyst such as platinum oxide or Raney nickel. Theintermediate piperidinomethylmalonate cyclizes to the octahydro- 3oxo-indolizinecarboxylate which is then reacted with a benzyl halide inthe presence of a metal hydride such as sodium hydride to produce thecorresponding 2-benzyl-2- indolizinecarboxylate. The benzyl substitutedester is then saponified in the presence of a basic catalyst, i.e., analkalior alkaline earth metal carbonate, oxide or hydroxide such aspotassium hydroxide or sodiumhydroxide to give the correspondingoctahydro-3-oxo-indolizinecar boxylic acid.

The octahydro-3-oxo-2-benzylindolizinecarboxylic acid, either in theform of the free acid or as the acid halide, may be ring closed. In thecase of the free acid, catalytic cyclodehydration is accomplished withan iuorganic acid such as polyphosphoric acid or hydrofluoric acid. Inthe case of the acid halide treatment with aluminum chloride causescyclization. In both cases hexahydro-oxospiro(indan indolizine)-one is'obtained which may be reduced to produce various hexahydroandoctahydro-hydroXyspiro-indan-indolizines. These in turn may beesterified by well-known acylationmethods to replace the hydroxy groupby a lower alkylcarbonyloxy group.

The reduction may be carried out with any one of a variety of well-knownreducing agents such as a complex metal hydride, i.e., sodiumborohydride, potassium borohydride or, preferably, lithium aluminumhydride in the presence of a solvent. Suitable solvents when a metalhydride is used are methanol, ethanol, 2-propanol and the like; where asif the reducing agent is lithium aluminum hydride, suitable solvents arean anhydrous ether, tetrahydrofuran, ethylene glycol dimethyl ether, andthe like.

The following examples are intended to illustrate, but not to limit thescope of the present invention.

Example I Z-pyridinecarboxaldehj de (107 parts byweight), dimethylmalonate (145 parts by weight), piperidine (8 parts by volume) andbenzoic acid (6.6- parts by Weight) are heated in benzene for 2.5 hourswith azeotropic distillation of water. The reaction solution is cooled,concentrated under reduced pressure, diluted with ether, washed withsodium bicarbonate solution and Water and dried. Removal of the solventsunder reduced pressure and trituration of the residue with aqueousmethanol gives 180 parts by weight of white plates, melting point 82 C.to 84 C. One recrystallization from aqueous methanol giveswhite plates,dimethyl 2-pyridylmethyleuemalonate, melting point 83.5 C. to 84.5 C;

Example 11 The diethyl homolog is prepared by the same method asdimethyl Z-pyridylmethylenemalonate starting with diethyl malonate. Thetwice distilled orange-brown liquid (81% yield, boiling point l57/0.5mm.) solidifies on standing. A sample of the free base converted to thesuifate salt andrecrystallized twice from ethanol-ether to give whiteneedles, diethyl Z-pyridylmethylenemalonate sulfate, melting point C. to101.5 C.

Example III To an ethereal solution of phenylmagnesium bromide (preparedfrom 196 parts by weight of bromobenzene and 30 parts by weightof'magnesium) a benzene solution of parts by weight of dimethylZ-pyridylmethylenemalou-ate is added dropwise over a period of oneand'o'nehalf hours, at 0 C. to 5 C. The reaction solution is stir-redfor two hours at 5 C., then poured into cold, dilute hydrochloric acid.The aqueous layer is withdrawn and partially neutralized with solidpotassium carbonate. The precipitated solid is filtered and ai-rd-rie-d,amounting to 81 parts by weight of a tan solid, melting point C. to C.(dec.). Recrystallization from ethanolether gives a white solid, meltingpoint C. to 178 C. (dec.). This material is dimethylpheuyl-Z-pyridyl-methylmalonate hydrochloride. Neutralization of itsaqueous solution affords the corresponding free base, subsequentlydescribed. The original filtrate of the hydrochloride salt is made basicwith potassium carbonate and extracted with ether, then with methylenechloride. Drying of the organic layers over magnesium sulfate andconcentration gives 20 parts by weight of a tan solid, melting point 95C. to 97 C. Recrystallization from petroleum etheret hyl acetate affordsa white solid, dimethyl phenyl-Z- pyridylmethylm-alonate, melting point97 C. to 98 C.

Example IV The procedure used for the preparation of dimethylphenyl-Z-pyridylmethylm-alon a'te is followed with the following amountsof materials: phenylmagnesium bromide from 70 parts by weight ofbromo'benzene and 10.7 parts. by weight of magnesium and diethylZ-p-yridylmethylenemalonate (511 parts by Weight). The product, isolatedas the free base, amounts, after one recrystallization from petroleumether, to 35 parts by weight of a white solid, melting point 715C. to 72C.

Example V A 10.8 parts by weight sample of diethyl 2-pyridyl- 'a mixtureof geometrical isomers.

methylenemalonate is reduced over 0.8 part 'by weight of platinum oxidein 100 partsby volume of -absolute,etha-' nol and 4 parts by volume ofglacial acetic acid under an initial pressure of 60 pounds/in. ofhydrogen. After seven hours, the theoretical amount-of hydrogen has beenconsumed and the hydrogen uptake stops. The reaction solution isfiltered and concentrated to dryness under reduced pressure using gentleheat. The concentrate,

j cooled in an ice bath, is made basic with 14 parts by volume of 35%sodium hydroxide and extracted with ether; The ether extracts arecombined, washed with water, dried and concentrated to dryness underreduced 3-oxo-2-indolizinecarboxylate as a yellow oil. After twodistillations, 6.2 parts by 'weight'of a pale yellowoil is I obtained,boiling point 110111/0.06 mm.

' 1 v Example VI A 22. 1 parts by weight sample of dimet-hy-l Z-pyridylmethylenem'alonate is reduced over 1.25 parts by Weight of platinumoxide catalyst in a solution of 150 parts by volume of ethanol and 10parts by volume of acetic acid.

, 'Theinitial pressure of hydrogen is 60 pounds/ink After thetheoretical amount of hydrogen is consumed, the catalyst is removed'byfiltration and the filtrateis concentnated to an oil which is distilled,giving 14.3 parts by weight of an oil, methyl octahydro3-oxo-2-indolizinecarboxylate, boiling point 138'145/=1 mm.

7 Example VII I, Toan ethanolic solution of dimethyl henylZ-pyridylmethylmalonate (10 parts by Weight) containing 10 parts byvolume of glacialacetic acid, is added 1 part by weight 7 of platinumoxide catalyst and the mixture ishydrogenated at room temperature at aninitial pressure of 51 pounds/ink After the theoretical amount ofhydrogen has been absorbed (three hours), the reaction mixture 'isfiltered. The filtrateis concentrated, diluted with ether,

washed with aqueous sodium bicarbonate, dried and concentrated.Trituration of the oily residue in petroleum ether-ether gives 6.1 partsby weight of the product as frompetroleum ether-ethyl acetate giveswhite crystals of methyl octahydro-3-oxo-1-phenyl-2-indolizinccarboxylate, melting point 84 C. to 89 C. A 0.330 part by weight sample ofsharp-melting octahydro-3-0xo-1 phenyl-Z-indolizinecarboxylic acid(melt- Tingpoint :166 .C. to 167 C.) is dissolved in methanol andtreated with diazomethane until the yellow color persists; The.solutionis then decolorized with a drop of acetic acid and concentrated.The residual semisolid is recrystallized from petroleum ether-ethylacetate to give 7 0.235 part by weight of. white prisms, methyl'ootahydro- 3 oxo 1-phenyl-2-ind-olizineoarboxylate, melting point11=3.5'C. to 114 C. The infrared spectrum of this material is verysimilar but not identical with the spectrum of the above-mentionedmixture of isomers.

Example VIII 7 1 'A solution :of 29.6 parts by weight of methyl octahy-I dro-3-oxo-2indolizinecarboxylate in 50 parts by volume of toluene isadded dropWise'ov-er fifteen minutes to a suspension of sodium hydride(8.3 parts by weight of i 54.7% sodium hydride in mineral oil is wellwashed with toluene to remove the mineral oil; the weight of activesodium hydride is assumed to be 4.5 parts by weight) in 250 parts byvolume of toluene After one hour reflux ing, the gas evolution cease-sand a solution of 25.3 parts by'weight of benZyl chloride -in 50.partsby volume of toluene is added dropwise to 'thestirred mixture at 100 7"acid. The aqueous acidic layer, along with some addipressure, giving8.9 parts 'by weight'of ethyl octahydro- A recrystallization C. Themixture is. stirred at reflux ier-"sixteen hours,

cooled and carefully treated with 5 parts 'by volume of absoluteethanol, then parts by volume 10f Water;

The organic layer is washed successively with 1-0%"sodium hydroxidesolution, water and dilute hydrochloric tiona'l concentratedhydrochloric acid, is added to. the combined aqueous and basic solutionsuntil the resulting pH is approximately 3. A solid, octahydroS-oxo-Q-benzyl-2-indolizinecarboxylic acid, separates, is collected by filtration,driedrand found to Weigh 6.3 parts by weight I (15% of the theoreticalamount of -octahydro 3-oxo-2- benzyl-2-indolizineearboxylic acid),melting point 170 C. (gas evolution).. The organic layer i rom the acid.ex-

traction is washed with water and dried by aze otropic distillation,which is continued'to remove all volatile 'material. The residualoilweighs 35.8' parts by weight.

A sample of the oil, methyl octahydro-3-oxo-2-benzyl-2-'indolizinecarboxylate,

is distilled, boiling point '-l60/0.2

Example IX To an aqueous me-thanolic solution of methyl octahy-' dro-3-oxo-1-phenyl=2 indolizinecarboxylate (35 parts by weight) is added'Sparts by weight of sodium hydroxide and the resulting solution isrefluxed for three hours. It is then concentrated, diluted withwat'erand extracted with ether. 7

chloride. After drying, the solvent is removed under reduced' ressureleaving 29.3 parts by'weight of' the crystalline product.Arecrystallization from ethyl acetate gives 7 the pure product as ,amixture of geometrical isomers,

octahydro 3 oxo 1 phenyl 2 indolizinecanboxylic acid, melting point 149C. to,153 C. f i

A portion of his mixture is recrystallized several times [from ethylacetate and gives a single, sharp-melting isomeric acid as smallwhiteprisms, melting point 166C.

to 167 7 C." The infrared spectrum ofthis material, 315:

though very similar, is not identical with the spectrum of the mixtureof isomers. r 1

' Example X I V In a similar manner ethyl octahydro-3 oxo-2-indolizinecanboxylate is hydrolyzed to give a .72% *crude yield of acid whichafter one recrystallization 'iromether-methylene chloride melts at C. to121 C. Tw o recrystalhzatrons from the same solvent mixturegiveasmallyield of crystals, octahydro-3-oxo-2-indolizinecarboxylicacid;

melting sharply at 123 C. to 124.5 C.

7 Example XI A mixture of 23 parts by weight of methyl octahydr'o3-oxo-2 benzyl 2-indolizinecarboxylate, 40 parts by volume of 95%ethanol and 50 parts by volume of 10% aqueous sodium hydroxide isrefluxed for five hours. A cloudiness is removed by filtration and thefiltrate is concentrated under reduced pressure almost to dryness}, Theslurry is dissolved in 125 parts by volume ofwater, the solution isextracted with ether, and the cooled aqueous layer is made stronglyacidic with concentrated hdrochloric acid. The cream colored solid whichis collected by filtration is thoroughly dried over-phosphorous ,pent-.ox1de to. give 16.9 parts by weight, melting point .175? C. (gasevolution), of octahydro-3-oxo-2-benzyl-2-indolizinecarboxyhc acid. Asample is recrystallized twice from ethyl acetate and is found to meltat 177 C. (gas evolu tion). a

V V 77 Example XII Methyl cctahydro carboxylate (10'.6 parts by weight)is'reduced with' 6.9 parts by weight of lithium aluminum hydride .by theprocedure described in Example XIII. A =4.7 parts by weight] sample ofthe resultingyellow oil (total yield"8.5.parts by weight) is treatedwith 1.2 parts by weight ot'tfuinar'ic acid in methanol; Theresulting'solid "is recrystallized. 1 several times from isopropylalcohol-ether to give a white solid, :octahydro 1 phenyl 2-indolizinemethanol fumarate, melting point 173* C. to 175 C. (dec;).

The aqueous layer is made acidic with con centrated hydrochloric acidand extracted with'methylene Example XIII To an ether suspension oflithium aluminum hydride (8.2 parts by weight) is added an etherealsolution of ethyl octahydro 3 oxo 1 phenyl 2 indolizinecarboxylate, 13.2parts by weight, over a period of one-half hour. The mixture is refluxedfor three and one-half hours, cooled and 24.5 parts by volume of wateradded cautiously. The solids are removed by filtration and the filtrate,after drying over magnesium sulfate, is concentrated to leave 8.5 partsby Weight of a slightly yellow oil. An ether solution of this oilallowed to react for fifty hours with methyl iodide. (5 parts byweight). The precipitated solid amounts to 7.3 parts by Weight. It isrecrystallized repeatedly from ethanol to afiord two fractions. Fraction(:1) amounts to 4.1 parts by weight of a mixture of isomers ofoctahydro-l-phenyl-Z- indolizinemethanol methiodide, melting point 218.5C. to 219.5 C.

Fraction (b) amounts to 0.8 part by weight of a single isomer ofoctahydro l-phenyl-Z-indolizinemethanol methiodide, melting point 184 C.to 186 0., whose infrared spectrum is similar to that of traction (a).

Example XIV A solution of 14.4 parts by weight of methyl octahydro-3-oxo-2 benzyl-2 indolizinecarboxylate in 5 parts by volume of ether isadded dropwise to a suspension of 5.7 parts by Weight of lithiumaluminum hydride in 200 parts by volume of ether. The stirred mixture isrefluxed overnight, then cooled and decomposed by the careful additionof 17 parts by volume of water. The inorganic solids are removed :byfiltration and the organic solution is washed with Water, dried andevaporated under reduced pressure to give 9.4 parts by Weight (77% oftheory) of oil. A sample of the oil is converted to its hydrochloridesalt which is recrystallized twice from 2-propanol to give whiteplatelets, 'octahydro-2-benzyl-2-indolizinemethanol hydrochloride,melting point 235 C. to 237 C.

Example XV To 0.2 part by weight of dry sodium methoxide and 6.8 partsby weight of octahydro-Z-indclizinemethanol suspended in 700 parts byvolume of n-heptane is added 10.6 parts by weight of ethyl benzilate.The mixture is refluxed for one hour and then 475 parts by volume ofliquid is removed by distillation. Ether, 150 parts by volume, is addedto the remaining residue and the resulting solution is extracted withdilute hydrochloric acid. Basification of the aqueous acid layer,extraction with ether, and evaporation of the ether layer to drynessgive 9.6 parts by weight of solid, melting point 98 C. to 102 C. Tworecrystallizations from heptane give 6.8 parts by Weight of crystals,octahydro-Z-indolizinemethyl benzilate, meltingpoint 104 C. to 106 C.

Example X VI The procedure for the preparation of octahydro-Z-indolizinemethyl benzilate is employed with 9 parts by Weight ofocta'hydrol-phenyl-2-indolizinemethanol and 9.5 parts by Weight of ethylbenzilate. Trituration of the crude product in hexane-ether gives 11.3parts by weight of a white solid, melting point 102 C. to 105 C. Arecrystallization from hexane gives a white solid, octahydro 1 phenylZ-indolizinemet-hyl *benzilate, melting point 108 C. to 109 C.

Example XVII A 7.2 parts by weight sample of octahydro-3-oxo-2-indolizinecarboxylic acid and 1.6 parts by Weight of sodium hydroxide in50 parts by volume of water-ethanol solution (3:2) is evaporated to agum and dried under high vacuum at 60 C. A benzene solution ofB-dimethylaminoethyl chloride (from trituration of 9.2 parts by Weightof the hydrochloride salt with sodium hyroxide pellets) is added to thedry sodium carboxylate suspended in 50 parts by volume of benzene. Themixture is refluxed for twenty-four hours, cooled and 1.7 parts byweight of sodium chloride removed by filtration. The filtrate isevaporated to give 8.8 parts by weight of oil which is distilled. Thelight yellow oily distillate (7.3 parts by weight) boils at 155 0.35 mm.The oily base is converted to the fumarate salt andrecrystallizedsuccessively from 2'-propanol-ether and ethanol-ether to give whitecrystals of Z-dimethylaminoethyl octahydro-3-oxo-2-indolizinecarboxylate fumarate, melting point 113 C. to 115 C.

Example XVIII Sodium octahydro-3 -oxo-1-phenyl-l-indolizinecarboxylateprepared from 6.8 parts byweight of the corresponding acid(octahydro-3-oxo-1-phenyl-2-indolizinecarboxylic acid) and 1.05 partsbyweight ofsodium hydroxide, is suspended in dry benzene and a benzenesolution of dimethylaminoethyl chloride (from 7.5 parts by weight of thecorresponding hydrochloride and 3.5 parts by weight of solid sodiumhydroxide) is added to the mixture, which is refluxedfor twenty-fivehours, then allowed to stir at room temperature for several days. Thereaction mixture is filtered, the 'filtrate is extracted with dilutehydrochloric acid, the aqueous layer made basic with solidpotassiumcarbonate and extracted with methylene chloride. After dryingthe solvent is removed leaving 6.1 parts by weight of a brown oil. Thecompound is then boiled in methanol, with fumaric acid, for three hours,concentrated and the residue crystallized from isopropyl alcohol-ethergiving 1.65 parts by weight of a white solid, 2-dimethylaminoethyloctahydro-3-oxo-1- phenyl-2-indolizinecarboxylate fumarate, meltingpoint C. to C. Several recrystallizations from isopropyl alcohol-etherraises the melting point to 161 C. to 163 C. 7

Example XIX To a benzene solution of octahydro-3-oxo-1phenyl-2-indolizinecarboxylic acid chloride, prepared from 6.5 parts by weight ofthe sodium salt of the corresponding acid and 2.9 parts by weight ofoxalyl chloride according to the procedure of G. I. Poos et al. [J Org.Chem., 26, 4898 (1961)] is added dropwise a solution of 1-methyl-4-hydroxypiperidine (3 parts by weight) in benzene. The resulting mixtureis stirred at room temperature for one hour then poured into cold dilutehydrochloric acid and washed with ether. The acidic layer is made basicwith potassium carbonate and extracted with ether. The other solution isdried and concentrated. The residual oil forms a fumarate salt whichafter three recrystallizations from ethanol-ether gives a white solid,(l-methyl-4- piperidyl) octahydro-3-oxo-1-phenyl-2-indolizinecarboxylatefumaratc, melting point 174 C. to 176 C.

Example XX A 16.8 parts by weight sample of ethyl octahydro-3-oxo-2-indolizinecarboxylate is added to a solution of 1.08 parts byweight of sodium methoxide in parts by volume of methanol. A 14.6 partsby'weight sample of 4-phenylpiperazine is then added and the solution isrefiuxed for twenty-eight hours. After addition of 0.5 'part by volumeof water, the solvents are removed by evaporation under reduced pressureto give a white solid. Recrystallization from benzene-petroleum ether(30 C. to 60 C.) gives 15.5 parts by weight of a white solid, octahydro3 oxo 2 (4 phenyl 1 piperaziny1carbonyl)- indolizine, melting point 153C. to 157 C. One recrystallization from ethyl acetate (Norite) giveswhite nacreous plates, melting point 162 C. to164 C.

Example XXI A 16.8 parts by weight sample of ethyl octahydro-3-oxo-2-indolizinecarboxylate is added toa solutionof 1.08 parts by weightof sodium methoxide in 40 parts by volume of methanol. A 14.0 parts byweight sample of noethyl)carbamoyllindolizine, weighs 9.5 parts byweight.

The oily base is converted to itshydrochloride salt and the salt, aftertwo recrystallizations'fro'm 2-propanolether solution, gives whitenacreous plates, melting point 174 C. to 176 C. v

' e p 7 7 Example XXII ,7 To a solution of sodium methoxide preparedfrom 0.57 part by weight of sodium in 50 parts by volume of methanol isadded a solution of methyl octahydro-3-oxo-2-indoliz inecarboxylate(19.7 parts by weight) in 50 parts by volume of methanol followed-by theaddition of damphetamine (15.0 parts by; Weight) in 50 parts by vol umeof methanol. 7 The solution is refluxed for twenty hours, then themethanol is removed under reduced pressure. The oil is distilled twiceto give octahydro-3-oxo-2- [N (a methylphenethyl)carbamoyl1indolizine,boiling point 185- 192" C./0.075 mm.

' Example XXI II V A benzene solution ofoctahydro-3-oxo-2-indolizinecarboxylic acid chloride'is preparedfrom.8.l parts by weight of the corresponding acid (octahydro-3-oxo-2-indolizinecarboxylic acid) via'the anhydrous sodium salt and 5.6 partsby weight of oxalyl chloride according to the procedure of G. I. Poos etal; [J. Org.'Chem., 26, 4898 (1961)]. To this solution is added dropwiseover twenty-five minutes asolution of 5.2' parts by weight of3-aminomethylpyridine. A solid begins to separate; parts by volume oftriethylamine is' added. The mixture is stirred overnight at roomtemperature then filtered from 8.4. parts by weight of insoluble salts.The filtrate is washed withwater, dried and evaporated under reducedpressureto give 2.4. parts by weight of. oil. The

aqueous washings arefco mbined and made basic. (pl-l 14) with 35% sodiumhydroxide solution. The mixture is extracted 'with benzene and theorganic layer is dried and evaporated under reduced pressure to give 7.8parts which is recrystallized from ether to give 5.5 parts by K weightof white crystals, octahydro-3-oXo-2-[N (3-pyr- Vidylmethyl)carbarnoyl1indolizine, melting'point 114 C.

V to '117 C. Succesive recrystallizations from ethyl acerate-hexane andethyl acetate-ether give white, crystals, melting point 115 C. "to 116.5.C.

Example XXIV indolizinecarboxylic acid chloride, prepared from 8 partsby weight of the sodium salt of the corresponding acid 8. boxylate, 2.57parts by weight of-oxalyl chloride and 5 parts by weight ofi-phenylpiperazine The crude product which amounts to 5.4 parts byweight is recrystallized from ethyl'aeetate to give a white solid,octahydro-3-oXo-- 1-phenyl-2-(4-phenyl 1 piperazinylcarbonyl)indolizine,

melting point 164 C. to 165 C.

V .ExampIeXXI I V The procedure described for the preparation ofoctahydro 3 oxo 1 phenyl 2 (1' pyrrolidinylcarbOnyDindolizine isemployed with 14 parts by. weight of sodium octahydro-30x0-1-phenyl-2-indolizinecarboxylate,

6.3' parts by weight ofeoxalyl chloride and 9 parts by; weight ofmorpholine. The crude product, which amounts f to 15.2 parts by weight,isrecrystallized twice fromethyl acetate to bive small white prisms,octahydro-S-oxo-L phenyl-Z-morpholinocarbonylindolizine, melting 1 point128" C.to129 c. r V

Example XXVII The procedure describedfor the preparation of beta hydro 3oxo- 1 phenyl -12 (1 pyrrolidinylcarbonyl)indolizine is employed with-6.6 parts by weight of sodiurn octahydro-3oXo-1-phenyl 2indolizinecarboxylate, 2.9 parts by weight of oxalyl chloride and 3.2parts by;

The crude product is 'refluxedin 5 aqueous methanolic sodium hydroxidefor weight of l-piperazineethanol.

amounts to 2.2 parts by weight which on recrystallizationfrom ethylacetate gives white crystals, octahydro-Is-oxol phenyl 2 [4 (2hydroxymethyl) 1 pipe'razinyl carbonyl]indolizine, melting point 179 C.to 180 C.

Example XXI/I171 A benzene solution of 6.6 parts'by weightof 'octa-jhydro 3 oxo 1 phenyl 2 L (1;- pyrrolidinylcar- V bonyl)indolizine isadded ,dropwiseto a stirred lithium To a benzene solution ofoctahyd'ro-i3-oxo-1-phenyl-2- and 3.58 parts by weight of oxalylchloride is added dropa wise a solution of pyrrolidine (3.98 parts byweight) in benzene. The resulting reaction solution is stirred at room.temperature for two hours, washed with dilute hydrochloric acid, driedand concentrated. The residual yellow solid is recrystallized from ethylacetate to give 6.6 parts by Weight of white needles,octahydro-3-oxo-1-'phenyl 2 (1- pyrrolidinylcarbonyl)indolizine, melting point 169 C. 'to170 C. r

7 Example XXV g r The procedure described for the preparation ofoctahydro 3 oxo 1 phenyl 2 (1 pyrrolidinylcar- '138/O.175 mm.

aluminum hydride suspension (4.1 parts by weight) in' ether and theresulting 'mixture is refiuxed for three hours. The mixture is thendecomposed with '12.parts by volume of water, filtered, and thefiltrate, after drying, concentrated. Saturation of an ethereal solutionof the oily residue with dry hydrogen chloride gives a hygroscopicsolid. After several recrystallizations from'etha noL ether, crystals ofthe dihydrochloride, octahydro-l-phenyl- 2-(l-pyrrolidinylmethyl)indolizine dihydrochloride, 'melting point 245.5 C.to 247 C.,' are obtained. I

Example XXIX The procedure described for the prepartion otiocta hydro 1phenyl 2 7 (1 pyrrolidinylmethyl) indelizine dihydrochloride is employedwith 1.8 parts by weight of octahydro 3 0X0 1 phenyl 2 morpholino'carbonylindolizine and 1.2 parts by weight of lithium aluminum hydride inether. The product is isolated as the dihydrochloride salt, octahydro 1phenyl-Z-morpholinomethylindolizine dihydrochloride, melting point 270?C. v

to 272 C. (dec.). a Example XXX A 70.6 parts by weight sample ofoctahydro -3 -oxo-2- benzyl-2-indolizinecarboxylic acid in an Erlenmeyerflask V 'is heated on the hot plate untilit melts and then for anadditional ten minutes until no more gas is evolved. 1'

the oil is. distilled twice to give a pale yellow oil, octaboilingathydro 3 0x0 2 benzylindolizine,

Example XXX] A solution of 15 parts by weight of octah ydro-3 oxo-,2-benzylindohzine in parts by volume of ether is added dropwise overfifteen minutes to a suspension of 7.4 parts by weight of lithiumaluminum hydride in 150 parts by volume of ether. The stirred mixture isrefluxed overnight, then cooled and decomposed by the careful additionof 23 parts by volume of water. The inorganic solids are removed byfiltration and the organic solution is washed with water, dried andconcentrated to dryness under reduced pressure to give 14 parts byweight of oil. This oil upon sitting at room temperature for six days ina stoppered flask deposits a viscous brown oil whose infrared spectrumsuggests a carbonate salt has formed. The pale yellow-tan supernatant isdistilled to give 9.7 parts by weight of colorless oil boiling at 97100/0.15 mm. A sample of the oily base is converted to the hexamate saltwhich is recrystallized from acetone-ether solution to give whitecrystals, octahydro-Z-benzylindolizine hexamate, melting point 108 C. to120 C.

Example XXXII A 4.5 parts by weight sample of octahydro-3-oxo-2-benzyl-Z-indolizinecarboxylic acid is added portionwise over twentyminutes to 66 parts by weight of polyphosphoric acid heated to 100 C.After three hours heating and stirring at 100 C. the slurry is cooledand poured onto crushed ice. After the ice melts, the aqueous solutionis extracted several times with ether-benzene and the combined organiclayer is washed with water, dried, and evaporated under reduced pressureto 4 parts by weight of oil which crystallizes, melting point 113 C. to117 C. One recrystallization from cyclohexane gives 2.8 parts by weightof crystals, melting point 119 C. to 121 C. A sample,1',5,6,7',8',8a-hexahydro-1- oxospiro(indan-2,2'-indolizin)-3(2H)-one,is recrystaliized to constant melting point, 121 C. to 122 C.

Example XXXIII A suspension of 7.7 parts by weight of 1, 5,6',7',8,8a'-hex-ahydro 1 oxospiro(indan-2,2'-indolizin)-3'(2'H)- one in 600 parts byvolume of ether is added rapidly to a suspension of 3.4 parts by weightof lithium aluminum hydride in 300 parts by volume of ether withcooling. The mixture is stirred at reflux for twenty hours, cooled, andcautiously treated with 10.4 parts by volume of water. After removal ofthe inorganic solids by filtration the filtrate is extracted with sodiumhydroxide solution, washed with water, dried, and evaporated to 5.6parts by weight of oil which crystallizes, melting point 107 C. to 117C. Two recrystallizations from benzenehexane give 3 parts by weight ofwhite crystals, octahydro- 1-hydroxyspiro(-indan-2,1-indolizine),melting point 110 C. to 122 C.

Example XXXIV A 5.1 parts by weight sample of 1',5',6',7',8,8ahexahydro1 oxospiro(indan-2,2'-indolizin)-3(2'H)- one in 50 parts by volume of2-propanol is added rapidly to a suspension of 0.76 part by weight ofsodium borohydride in parts by volume of Z-propanol at room temperature.The mixture is stirred at reflux for two hours then cooled in an icebath and treated with 125 parts by volume of 2.9 M hydrochloric acid.The 2- propanol is removed under reduced pressure and the mixture isextracted several times with ether-benzene solution. The combinedorganic solution is washed with water, dried, and evaporated underreduced pressure to 3.8 parts by weight of an oil, which partiallycrystallizes on standing. The aqueous acid layer is made basic with 35%sodium hydroxide solution and extracted with methylene chloride. Theorganic layer is washed with water, dried and evaporated under reducedpressure to an oil (0.6 part by weight). The combined oil iscrystallized from benzene-hexane solution to give 3.3 parts by weight ofwhite crystals, melting point 116 C. to 128 C. One recrystallizationfrom cyclohexane-hexane solution followed by two recrystallizations fromcyclohexane gives 2.4 parts by weight of white crystals of mixedcrystalline form of1,5,6,7,8',8a'-hexahydro-1-hydroxyspiro(indan-2,2-indolizine)-3(2'H)-one,clusters of feathery needles, melting point 137 C. to 142 C. and largerirregular prisms, melting point 151 C. to 155 C.

The mother liquor from the recrystallization of the mixture ofstereoisomers is concentrated and the resulting solid is recrystallizedtwice from cyclohexane to give 0.200 part by weight of a single isomeras white irregular prisms,1,5',6',7,8,8a-hexahydro-l-hydroxyspiro(indan-2,2'-indolizin)-3(2H)-one, melting point 154 C. to

156 C. A mixed melting point with the isomeric mixture is depressed.

What is claimed is:

1. The compound wherein R is a member selected from the group consistingof oxo and hydrogen, and R is a member selected from the groupconsisting of hydrogen, oxo, hydroxy and lower alkyicarbonyloxy having 1to 7 carbon atoms.

3. 1',5',6',7',8,8a-hexahydro- 1 hydroxyspiro (indan- 2,2'-indol-izine)3 2'H) -one.

4. Octahydro-l-hydroxyspiro(indan-2,2-indolizine).

No references cited.

IRVING MARCUS, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No,3,189,611 June 15, 1965 Richard Joseph Mohrbache r It is herebycertified that error appears in the above numbered patent requiringcorrection and that th e said Letters Patent should read as correctedbelow.

Column 6, line 14,

for "phenyl-l" read phenyl2- column 8 line 16, for "b n u lve" read giveSigned and sealed this 7th day of December 1965.

(SEAL) Allest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. THE COMPOUND